4. A pharmaceutical composition comprising a therapeutically effective
amount of a compound according to claim 1, or a pharmaceutically
acceptable salt thereof, and at least one pharmaceutically acceptable
excipients, carriers or diluents.

5-7. (canceled)

8. A method comprising treating pain in a warm-blooded animal by
administering to said animal in need of such treatment a therapeutically
effective amount of a compound according to claim 1, or a
pharmaceutically acceptable salt thereof.

9. A method comprising treating pain in a warm-blooded animal by
administering to said animal in need of such treatment a pharmaceutical
composition according to claim 4.

10. The method according to claim 8 or 9, wherein said pain is
neuropathic pain.

11-12. (canceled)

13. A pharmaceutical composition comprising a therapeutically effective
amount of a compound according to claim 2, and at least one
pharmaceutically acceptable excipient, carrier, or diluent.

14. A method comprising treating pain in a warm-blooded animal by
administering to said animal in need of such treatment a therapeutically
effective amount of a compound according to claim 2.

15. A method comprising treating pain in a warm-blooded animal by
administering to said animal in need of such treatment a pharmaceutical
composition according to claim 13.

16. The method according to claim 14 or 15, wherein said pain is
neuropathic pain.

Description:

[0001] The present invention relates to pharmaceutical compositions, which
comprise compounds that act via antagonism of the CCR2b receptor for
which MCP-1 is one of the known ligands and so may be used to treat
inflammatory disease and/or neuropathic pain, which is mediated by these
receptors. The invention further relates to novel compounds for use in
the compositions, to processes for their preparation, to intermediates
useful in their preparation and to their use as therapeutic agents.

[0002] Chemokines play an important role in immune and inflammatory
responses in various diseases and disorders, including rheumatoid
arthritis, chronic obstructive pulmonary disease, atherosclerosis and
other autoimmune pathologies such as inflammatory bowel disease,
diabetes, asthma and allergic diseases. Chemokines also have a role in
neuropathic pain, angiogenesis and modulation of chemokines may be
beneficial in the treatment of cancer. Chemokines are small secreted
molecules belonging to a is growing superfamily of 8-14 kDa proteins
characterized by a conserved four cysteine motif. The chemokine
superfamily can be divided into two main groups exhibiting characteristic
structural motifs, the Cys-X-Cys (C-X-C) and Cys-Cys (C-C) families.
These are distinguished on the basis of a single amino acid insertion
between the NH-proximal pair of cysteine residues and sequence
similarity.

[0003] The C-C chemokines include potent chemoattractants of monocytes and
lymphocytes such as monocyte chemoattractant proteins 1-3 (MCP-1, MCP-2
and MCP-3), RANTES (Regulated on activation, Normal T expressed and
Secreted), eotaxin and the macrophage inflammatory proteins 1α and
1β (MIP-1α and MIP-1β).

[0004] The C-X-C chemokines include several potent chemoattractants and
activators of neutrophils such as interleukin-8 (IL-8) and
neutrophil-activating peptide 2 (NAP 2).

[0005] Studies have demonstrated that the actions of chemokines are
mediated by subfamilies of G-protein coupled receptors, among which there
are the receptors designated CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7,
CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5 and CX3CR1. These
receptors represent good targets for drug development since agents, which
modulate these receptors would be useful in the treatment of disorders
and diseases such as those mentioned above.

[0007] The present invention relates to a compound of formula (I) as a
base or as a pharmaceutically acceptable salt thereof,

##STR00002##

wherein P is a phenyl or a monocyclic or bicyclic heteroaryl having up to
9 ring atoms and comprising up to 3 heteroatoms independently selected
from N, O, and S, wherein the phenyl or the heteroaryl is optionally
substituted by up to 3 substituents independently selected from halogen,
cyano, CF3, SC1-4 haloalkyl, SC1-4 alkyl, OC1-4
haloalkyl, OC1-4alkyl, OC1-4 alkylphenyl, C1-4 alkyl,
C3-4 cycloalkyl, C1-3 alkoxy, C1-3 thioalkoxy,
pentafluoroethyl, pentafluoroethoxy, phenyl, phenC1-4alkyl,
phenC1-4alkoxy, phenC1-4alkoxyC1-4alkyl, heteroaryl,
heteroC1-4alkyl, heteroC1-3alkoxy, and
heteroC1-3alkoxyC1-4alkyl, wherein any substituent heteroaryl
has up to 6 ring atoms and comprises up to 3 heteroatoms independently
selected from N, O and S, wherein any substituent phenyl or heteroaryl
ring is optionally substituted by up to 3 substituents independently
selected from halogen, C1-4 alkyl, C3-4 cycloalkyl, C1-3
alkoxy, C1-3 thioalkoxy, pentafluoroethyl, pentafluoroethoxy, and
cyano, wherein any alkyl or alkoxy is optionally substituted by up to
three halogens; R1 is C1-4 alkyl; and m is 0, 1 or 2; and
provided the formula I compound is not
4-[4-tert-butylpiperazin-2-yl)carbonyl]-N-(3,4-dichlorophenyl)piperazine--
1-carboxamide.

[0008] Another embodiment relates to a compound according to formula (I)
as a base or as a pharmaceutically acceptable salt thereof, wherein P is
a phenyl or a monocyclic heteroaryl having up to 9 ring atoms and
comprising up to 3 heteroatoms independently selected from N, O and S,
wherein the phenyl or the heteroaryl is optionally substituted by up to 3
substituents independently selected from halogen, cyano, CF3,
SC1-4 haloalkyl, SC1-4 alkyl, OC1-4 haloalkyl,
OC1-4alkyl, OC1-4 alkylphenyl, C1-4 alkyl, C3-4
cycloalkyl, C1-3 alkoxy, C1-3 thioalkoxy, pentafluoroethyl,
pentafluoroethoxy, phenyl, phenC1-4alkyl, phenC1-4alkoxy,
phenC1-4alkoxyC1-4alkyl, heteroaryl, heteroC1-4alkyl,
heteroC1-3alkoxy, and heteroC1-3alkoxyC1-4alkyl, wherein
any substituent heteroaryl has up to 6 ring atoms and comprises up to 3
heteroatoms independently selected from N, O and S, and any substituent
phenyl or heteroaryl ring is optionally substituted by up to 3
substituents independently selected from halogen, C1-4 alkyl,
C3-4 cycloalkyl, C1-3 alkoxy, C1-3 thioalkoxy,
pentafluoroethyl, pentafluoroethoxy, and cyano; wherein any alkyl or
alkoxy is optionally substituted by up to three halogens; R1 is
C1-4 alkyl; and m is 0, 1 or 2.

[0009] A further embodiment relates to a compound according to formula (I)
as a base or as a pharmaceutically acceptable salt thereof, wherein P is
a phenyl or a monocyclic heteroaryl having up to 9 ring atoms and
comprising up to 3 heteroatoms independently selected from N, O and S,
wherein the phenyl or the heteroaryl is optionally substituted by up to 3
substituents independently selected from halogen, cyano, CF3,
SC1-4 haloalkyl, SC1-4 alkyl, OC1-4 haloalkyl,
OC1-4alkyl, OC1-4 alkylphenyl, C1-4 alkyl, C3-4
cycloalkyl, C1-3 alkoxy, C1-3 thioalkoxy, pentafluoroethyl,
pentafluoroethoxy, phenyl, phenC1-4alkyl, phenC1-4alkoxy,
phenC1-4alkoxyC1-4alkyl, heteroaryl, heteroC1-4alkyl,
heteroC1-3alkoxy, and heteroC1-3alkoxyC1-4alkyl; R1
is C1-4 alkyl; and m is 0 or 1.

[0011] A yet further embodiment relates to a compound according to formula
(I) as a base or as a pharmaceutically acceptable salt thereof, wherein P
is phenyl optionally substituted by up to 3 substituents independently
selected from halogen, cyano, CF3, SC1-4 haloalkyl, OC1-4
haloalkyl, OC1-4 alkylphenyl, C1-4 alkyl, C3-4 cycloalkyl,
C1-3 alkoxy, C1-3 thioalkoxy, and pentafluoroethyl.

[0012] A still yet further embodiment relates to a compound according to
formula (I) as a base or as a pharmaceutically acceptable salt thereof,
wherein P is phenyl substituted by up to 3 substituents independently
selected from halogen, cyano, CF3, SC1-4 haloalkyl, OC1-4
haloalkyl, OC1-4 alkylphenyl, and C1-4 alkyl.

[0013] According to another embodiment, P is phenyl.

[0014] In still another embodiment, said phenyl is substituted by 2
substituents selected from halogen.

[0015] In yet another embodiment, said halogens are selected from chloro
and fluoro.

[0016] Another embodiment relates to a compound according to formula (I)
as a base or as a pharmaceutically acceptable salt thereof, wherein P is
a monocyclic heteroaryl having up to 6 ring atoms and comprising up to 3
heteroatoms independently selected from N, O and S, wherein said
heteroaryl is optionally substituted by up to 3 substituents
independently selected from halogen, cyano, CF3, SC1-4
haloalkyl, SC1-4 alkyl, OC1-4 haloalkyl, OC1-4alkyl,
OC1-4 alkylphenyl, C1-4 alkyl, C3-4 cycloalkyl, C1-3
alkoxy, C1-3 thioalkoxy, pentafluoroethyl, pentafluoroethoxy,
phenyl, phenC1-4alkyl, phenC1-4alkoxy, and
phenC1-4alkoxyC1-4alkyl.

[0018] In an even still yet further embodiment, said monocyclic heteroaryl
is substituted by up to 3 substituents independently selected from
halogen, cyano, CF3, SC1-4 haloalkyl, OC1-4 haloalkyl,
OC1-4 alkylphenyl, and C1-4 alkyl. Another embodiment relates
to a compound according to formula (I) as a base or as a pharmaceutically
acceptable salt thereof, wherein m is 0.

[0019] Yet another embodiment relates to a compound according to formula
(I) as a base or as a pharmaceutically acceptable salt thereof, wherein P
is a phenyl or a monocyclic heteroaryl having up to 5 ring atoms and
comprising up to 3 heteroatoms independently selected from N, O and S,
wherein the phenyl or the heteroaryl is optionally substituted by up to 3
substituents independently selected from halogen, cyano, CF3,
SC1-4 haloalkyl, SC1-4 alkyl, OC1-4 haloalkyl,
OC1-4alkyl, OC1-4 alkylphenyl, and C1-4 alkyl; and m is 0.

[0021] Compounds of formula (I) as a base or a pharmaceutically acceptable
salt thereof can be used in the treatment of diseases in which the
chemokine receptor belongs to the C-C receptor subfamily. In, for
example, one scenario the target chemokine receptor is the CCR2 receptor.

[0022] CCR2 is a receptor for the Monocyte chemoattractant protein-1
(MCP-1). MCP-1 is a member of the chemokine family of pro-inflammatory
proteins that mediate leukocyte chemotaxis and activation. MCP-1 is a C-C
chemokine that is a potent T-cell and monocyte chemoattractant. MCP-1 has
been implicated in the pathophysiology of a large number of inflammatory
diseases including, for example, rheumatoid arthritis, chronic
obstructive pulmonary disease, atherosclerosis, inflammatory bowel
disease, and neuropathic pain.

[0023] MCP-1 acts through the CCR2 receptor. MCP-2, MCP-3 and MCP-4 may
also act, at least in part, through this receptor. Therefore in this
specification, when reference is made to "inhibition or antagonism of
MCP-1" or "MCP-1 mediated effects" this includes inhibition or antagonism
of MCP-2 and/or MCP-3 and/or MCP-4 mediated effects when MCP-2 and/or
MCP-3 and/or MCP-4 are acting through the CCR2 receptor.

[0026] The term "Cm-n" or "Cm-n group" refers to any group
having m to n carbon atoms.

[0027] As used herein, "alkyl", used alone or as a suffix or prefix, is
intended to include both branched and straight chain saturated aliphatic
hydrocarbon groups having from 1 to 12 carbon atoms or if a specified
number of carbon atoms is provided then that specific number would be
intended. For example "C1-6 alkyl" denotes alkyl having 1, 2, 3, 4,
5 or 6 carbon atoms. Examples of alkyl include, but are not limited to,
methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl,
pentyl, and hexyl. In the case where a subscript is the integer 0 (zero)
the group to which the subscript refers to indicates that the group may
be absent, i.e. there is a direct bond between the groups.

[0028] The term "alkoxy", unless stated otherwise, refers to radicals of
the general formula --O--R, wherein R is selected from a hydrocarbon
radical. For example "C1-6 alkoxy" denotes alkoxy having 1, 2, 3, 4,
5 or 6 carbon atoms. Examples of alkoxy include, but are not limited to,
methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy and isobutoxy.

[0029] As used herein, "alkenyl", used alone or as a suffix or prefix, is
intended to include both branched and straight chain aliphatic
hydrocarbon groups comprising at least one carbon-carbon double bond
(--C═C--) and having from 2 to 12 carbon atoms or if a specified
number of carbon atoms is provided then that specific number would be
intended. For example "C2-6 alkenyl" denotes alkenyl having 2, 3, 4,
5 or 6 carbon atoms.

[0030] As used herein, "alkynyl", used alone or as a suffix or prefix, is
intended to include both branched and straight chain aliphatic
hydrocarbon groups comprising at least one carbon-carbon triple bond
(--C≡C--) and having from 2 to 12 carbon atoms or if a specified
number of carbon atoms is provided then that specific number would be
intended. For example "C2-6 alkynyl" denotes alkynyl having 2, 3, 4,
5 or 6 carbon atoms.

[0031] The term "halo" includes fluoro, chloro, bromo and iodo. References
to aryl groups include aromatic carbocylic groups such as phenyl and
naphthyl.

[0033] "Heteroaryl" refers to those heterocyclyl groups described above
which has an aromatic character. The term "aralkyl" refers to aryl
substituted alkyl groups such as benzyl. The terms "aryl" and
"heteroaryl" include non-condensed ring systems such as biphenyl.

[0034] As used herein, "pharmaceutically acceptable salts" refer to
derivatives of the disclosed compounds wherein the parent compound is
modified by making acid or base salts thereof. Examples of
pharmaceutically acceptable salts include, but are not limited to,
mineral or organic acid salts of basic residues such as amines; alkali or
organic salts of acidic residues such as carboxylic acids; and the like.
The pharmaceutically acceptable salts include the conventional non-toxic
salts or the quaternary ammonium salts of the parent compound formed, for
example, from non-toxic inorganic or organic acids. For example, such
conventional non-toxic salts include those derived from inorganic acids
such as hydrochloric acid.

[0035] The pharmaceutically acceptable salts of the present invention can
be synthesized from the parent compound that contains a basic or acidic
moiety by conventional chemical methods. Generally, such salts can be
prepared by reacting the free acid or base forms of these compounds with
a stoichiometric amount of the appropriate base or acid in water or in an
organic solvent, or in a mixture of the two; generally, nonaqueous media
like diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile
are used.

[0036] Compounds of the invention show unexpected properties when compared
to compounds disclosed in for example WO-2006/067401. For example, a
compound of the invention may have increased potency and/or increased
margins vs hERG.

[0037] The compounds of Formula I and pharmaceutically acceptable salts
thereof may be prepared as follows:

(a) by the reaction of a compound of Formula (II),

##STR00003##

wherein PG is a protecting group, for example, benzyloxycarbonyl, benzyl
or tert-butyloxycarbonyl with an isocyanate of Formula (III)

P--N═C═O (III)

or, with a carbamate of Formula (IV).

##STR00004##

wherein P is defined above, followed by removal of the protecting group
or (b) by the amide coupling of a compound of Formula (V),

##STR00005##

wherein PG is a protecting group, with a compound of Formula (VI)

##STR00006##

wherein P is defined above, followed by removal of the protecting group,
and, if required, by conversion to a pharmaceutically acceptable salt
thereof.

[0038] When the protecting group is benzyloxycarbonyl or benzyl then
removal can be effected by hydrogenation (for example hydrogen in the
presence of palladium on carbon catalyst). When the protecting group is
tert-butyloxycarbonyl removal may be effected by treatment with acid
(such as hydrochloric acid or trifluoroacetic acid).

[0039] Convenient protecting groups and details of processes for adding
and removing such groups may be found in "Protective Groups in Organic
Synthesis", 3rd Edition (1999) by Greene and Wuts.

[0040] The compounds of Formula I may be prepared as follows:

##STR00007##

[0041] A compound of formula (I), as a base or a pharmaceutically
acceptable salt thereof, may be used in the treatment of:

[0042] The invention further provides a compound of Formula (I) as defined
above for use in the treatment of C-C-chemokine mediated disease such as
inflammatory disease. When used in this way, the compounds are suitably
formulated into pharmaceutical compositions, which further contain a
pharmaceutically acceptable carrier and these form a further aspect of
the invention. The compound is conveniently used for the treatment of
CCR2b mediated inflammatory diseases and/or neuropathic pain.

[0043] The compounds of the present invention may be used in the treatment
of neuropathic pain associated with a C-C chemokine mediated disease,
condition or disorder such as those listed hereinbefore. In particular
compounds of the invention may be used in the treatment of neuropathic
pain associated with a CCR2b chemokine mediated disease, condition or
disorder. The compounds of the present invention may also be use in the
treatment of acute pain, chronic pain, back pain, cancer pain, and
visceral pain.

[0045] In particular compounds of the invention may be used to treat
neuropathic pain associated with arthritis and in particular
osteoarthritis.

[0046] Furthermore, the invention provides the use of a compound of
Formula (I) as defined above in the preparation of a medicament for
treating C-C chemokine mediated disease, and in particular for the
treatment of CCR2b mediated inflammatory diseases.

[0047] The invention further relates to combination therapies wherein a
compound of the invention, or a pharmaceutically acceptable salt thereof,
or a pharmaceutical composition or formulation comprising a compound of
the invention, is administered concurrently or sequentially or as a
combined preparation with another therapeutic agent or agents, for the
treatment of one or more of the conditions listed.

[0048] In particular, for the treatment of the inflammatory diseases such
as (but not restricted to) rheumatoid arthritis, osteoarthritis, asthma,
allergic rhinitis, chronic obstructive pulmonary disease (COPD),
psoriasis, neuropathic pain and inflammatory bowel disease, the compounds
of the invention may be combined with agents listed below.

[0050] The present invention still further relates to the combination of a
compound of the invention, or a pharmaceutically acceptable salt thereof,
together with a cytokine or agonist or antagonist of cytokine function,
(including agents which act on cytokine signalling pathways such as
modulators of the SOCS system) including alpha-, beta-, and
gamma-interferons; insulin-like growth factor type I (IGF-1);
interleukins (IL) including IL1 to 17, and interleukin antagonists or
inhibitors such as anakinra; tumour necrosis factor alpha (TNF-α)
inhibitors such as anti-TNF monoclonal antibodies (for example
infliximab; adalimumab, and CDP-870) and TNF receptor antagonists
including immunoglobulin molecules (such as etanercept) and
low-molecular-weight agents such as pentoxyfylline.

[0051] In addition the invention relates to a combination of a compound of
the invention, or a pharmaceutically acceptable salt thereof, with a
monoclonal antibody targeting B-Lymphocytes (such as CD20 (rituximab),
MRA-aIL16R and T-Lymphocytes, CTLA4-Ig, HuMax Il-15).

[0052] The present invention still further relates to the combination of a
compound of the invention, or a pharmaceutically acceptable salt thereof,
with a modulator of chemokine receptor function such as an antagonist of
CCR1, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the
C-C family); CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family)
and CX3CR1 for the C-X3-C family.

[0053] The present invention further relates to the combination of a
compound of the invention, or a pharmaceutically acceptable salt thereof,
with an inhibitor of matrix metalloprotease (MMPs), i.e., the
stromelysins, the collagenases, and the gelatinases, as well as
aggrecanase; especially collagenase-1 (MMP-1), collagenase-2 (MMP-8),
collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10),
and stromelysin-3 (MMP-11) and MMP-9 and MMP-12, including agents such as
doxycycline.

[0054] The present invention still further relates to the combination of a
compound of the invention, or a pharmaceutically acceptable salt thereof,
and a leukotriene biosynthesis inhibitor, 5-lipoxygenase (5-LO) inhibitor
or 5-lipoxygenase activating protein (FLAP) antagonist such as; zileuton;
ABT-761; fenleuton; tepoxalin; Abbott-79175; Abbott-85761; a
N-(5-substituted)-thiophene-2-alkylsulfonamide;
2,6-di-tert-butylphenolhydrazones; a methoxytetrahydropyrans such as
Zeneca ZD-2138; the compound SB-210661; a pyridinyl-substituted
2-cyanonaphthalene compound such as L-739,010; a 2-cyanoquinoline
compound such as L-746,530; or an indole or quinoline compound such as
MK-591, MK-886, and BAY x 1005.

[0055] The present invention further relates to the combination of a
compound of the invention, or a pharmaceutically acceptable salt thereof,
and a receptor antagonist for leukotrienes (LT) B4, LTC4, LTD4, and LTE4.
Selected from the group consisting of the phenothiazin-3-1s such as
L-651,392; amidino compounds such as CGS-25019c; benzoxalamines such as
ontazolast; benzenecarboximidamides such as BIIL 284/260; and compounds
such as zafirlukast, ablukast, montelukast, pranlukast, verlukast
(MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY x 7195.

[0056] The present invention still further relates to the combination of a
compound of the invention, or a pharmaceutically acceptable salt thereof,
and a phosphodiesterase (PDE) inhibitor such as a methylxanthanine
including theophylline and aminophylline; a selective PDE isoenzyme
inhibitor including a PDE4 inhibitor an inhibitor of the isoform PDE4D,
or an inhibitor of PDE5.

[0057] The present invention further relates to the combination of a
compound of the invention, or a pharmaceutically acceptable salt thereof,
and a histamine type 1 receptor antagonist such as cetirizine,
loratadine, desloratadine, fexofenadine, acrivastine, terfenadine,
astemizole, azelastine, levocabastine, chlorpheniramine, promethazine,
cyclizine, or mizolastine; applied orally, topically or parenterally.

[0058] The present invention still further relates to the combination of a
compound of the invention, or a pharmaceutically acceptable salt thereof,
and a proton pump inhibitor (such as omeprazole) or a gastroprotective
histamine type 2 receptor antagonist.

[0059] The present invention further relates to the combination of a
compound of the invention, or a pharmaceutically acceptable salt thereof,
and an antagonist of the histamine type 4 receptor.

[0060] The present invention still further relates to the combination of a
compound of the invention, or a pharmaceutically acceptable salt thereof,
and an alpha-1/alpha-2 adrenoceptor agonist vasoconstrictor
sympathomimetic agent, such as propylhexedrine, phenylephrine,
phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline
hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline
hydrochloride, xylometazoline hydrochloride, tramazoline hydrochloride or
ethylnorepinephrine hydrochloride.

[0061] The present invention further relates to the combination of a
compound of the invention, or a pharmaceutically acceptable salt thereof,
and an anticholinergic agents including muscarinic receptor (M1, M2, and
M3) antagonist such as atropine, hyoscine, glycopyrrrolate, ipratropium
bromide, tiotropium bromide, oxitropium bromide, pirenzepine or
telenzepine.

[0062] The present invention still further relates to the combination of a
compound of the invention, or a pharmaceutically acceptable salt thereof,
and a beta-adrenoceptor agonist (including beta receptor subtypes 1-4)
such as isoprenaline, salbutamol, formoterol, salmeterol, terbutaline,
orciprenaline, bitolterol mesylate, or pirbuterol, or a chiral enantiomer
thereof.

[0063] The present invention further relates to the combination of a
compound of the invention, or a pharmaceutically acceptable salt thereof,
and a chromone, such as sodium cromoglycate or nedocromil sodium.

[0064] The present invention still further relates to the combination of a
compound of the invention, or a pharmaceutically acceptable salt thereof,
with a glucocorticoid, such as flunisolide, triamcinolone acetonide,
beclomethasone dipropionate, budesonide, fluticasone propionate,
ciclesonide or mometasone furoate.

[0065] The present invention further relates to the combination of a
compound of the invention, or a pharmaceutically acceptable salt thereof,
with an agent that modulates a nuclear hormone receptor such as PPARs,
for example rosiglitazone.

[0066] The present invention further relates to the combination of a
compound of the invention, or a pharmaceutically acceptable salt thereof
with gabapentin, lidoderm, pregablin and equivalents and pharmaceutically
active isomer(s) and metabolite(s) thereof.

[0067] The present invention further relates to the combination of a
compound of the invention, or a pharmaceutically acceptable salt thereof
with celecoxib, etoricoxib, lumiracoxib, rofecoxib, valdecoxib,
diclofenac, loxoprofen, naproxen, paracetamol and equivalents and
pharmaceutically active isomer(s) and metabolite(s) thereof.

[0068] The present invention still further relates to the combination of a
compound of the invention, or a pharmaceutically acceptable salt thereof,
together with an immunoglobulin (Ig) or Ig preparation or an antagonist
or antibody modulating Ig function such as anti-IgE (for example
omalizumab).

[0069] The present invention further relates to the combination of a
compound of the invention, or a pharmaceutically acceptable salt thereof,
and another systemic or topically-applied anti-inflammatory agent, such
as thalidomide or a derivative thereof, a retinoid, dithranol or
calcipotriol.

[0070] The present invention still further relates to the combination of a
compound of the invention, or a pharmaceutically acceptable salt thereof,
and combinations of aminosalicylates and sulfapyridine such as
sulfasalazine, mesalazine, balsalazide, and olsalazine; and
immunomodulatory agents such as the thiopurines, and corticosteroids such
as budesonide.

[0071] The present invention further relates to the combination of a
compound of the invention, or a pharmaceutically acceptable salt thereof,
together with an antibacterial agent such as a penicillin derivative, a
tetracycline, a macrolide, a beta-lactam, a fluoroquinolone,
metronidazole, an inhaled aminoglycoside; an antiviral agent including
acyclovir, famciclovir, valaciclovir, ganciclovir, cidofovir, amantadine,
rimantadine, ribavirin, zanamavir and oseltamavir; a protease inhibitor
such as indinavir, nelfinavir, ritonavir, and saquinavir; a nucleoside
reverse transcriptase inhibitor such as didanosine, lamivudine,
stavudine, zalcitabine or zidovudine; or a non-nucleoside reverse
transcriptase inhibitor such as nevirapine or efavirenz.

[0072] The present invention still further relates to the combination of a
compound of the invention, or a pharmaceutically acceptable salt thereof,
and a cardiovascular agent such as a calcium channel blocker, a
beta-adrenoceptor blocker, an angiotensin-converting enzyme (ACE)
inhibitor, an angiotensin-2 receptor antagonist; a lipid lowering agent
such as a statin or a fibrate; a modulator of blood cell morphology such
as pentoxyfylline; thrombolytic, or an anticoagulant such as a platelet
aggregation inhibitor.

[0073] The present invention further relates to the combination of a
compound of the invention, or a pharmaceutically acceptable salt thereof,
and a CNS agent such as an antidepressant (such as sertraline), an
anti-Parkinsonian drug (such as deprenyl, L-dopa, ropinirole,
pramipexole, a MAOB inhibitor such as selegine and rasagiline, a comP
inhibitor such as tasmar, an A-2 inhibitor, a dopamine reuptake
inhibitor, an NMDA antagonist, a nicotine agonist, a dopamine agonist or
an inhibitor of neuronal nitric oxide synthase), or an anti-Alzheimer's
drug such as donepezil, rivastigmine, tacrine, a COX-2 inhibitor,
propentofylline or metrifonate.

[0074] The present invention still further relates to the combination of a
compound of the invention, or a pharmaceutically acceptable salt thereof,
and an agent for the treatment of acute or chronic pain, such as a
centrally or peripherally-acting analgesic (for example an opioid or
derivative thereof), carbamazepine, gabapentin, pregabalin, phenyloin,
sodium valproate, amitryptiline or other anti-depressant agent-s,
paracetamol, CB 1 agonist, muscarinic agonist, TRPV-1 antagonist, mGluR5
agonist or a non-steroidal anti-inflammatory agent.

[0075] The present invention further relates to the combination of a
compound of the invention, or a pharmaceutically acceptable salt thereof,
together with a parenterally or topically-applied (including inhaled)
local anaesthetic agent such as lignocaine or a derivative thereof.

[0076] A compound of the present invention, or a pharmaceutically
acceptable salt thereof, can also be used in combination with an
anti-osteoporosis agent including a hormonal agent such as raloxifene, or
a biphosphonate such as alendronate.

[0078] A compound of the invention, or a pharmaceutically acceptable salt
thereof, can also be used in combination with an existing therapeutic
agent for the treatment of cancer, for example suitable agents include:

(i) an antiproliferative/antineoplastic drug or a combination thereof, as
used in medical oncology, such as an alkylating agent (for example
cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan,
chlorambucil, busulphan or a nitrosourea); an antimetabolite (for example
an antifolate such as a fluoropyrimidine like 5-fluorouracil or tegafur,
raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, gemcitabine
or paclitaxel); an antitumour antibiotic (for example an anthracycline
such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin,
idarubicin, mitomycin-C, dactinomycin or mithramycin); an antimitotic
agent (for example a vinca alkaloid such as vincristine, vinblastine,
vindesine or vinorelbine, or a taxoid such as taxol or taxotere); or a
topoisomerase inhibitor (for example an epipodophyllotoxin such as
etoposide, teniposide, amsacrine, topotecan or a camptothecin); (ii) a
cytostatic agent such as an antioestrogen (for example tamoxifen,
toremifene, raloxifene, droloxifene or iodoxyfene), an oestrogen receptor
down regulator (for example fulvestrant), an antiandrogen (for example
bicalutamide, flutamide, nilutamide or cyproterone acetate), a LHRH
antagonist or LHRH agonist (for example goserelin, leuprorelin or
buserelin), a progestogen (for example megestrol acetate), an aromatase
inhibitor (for example as anastrozole, letrozole, vorazole or exemestane)
or an inhibitor of 5α-reductase such as finasteride; (iii) an agent
which inhibits cancer cell invasion (for example a metalloproteinase
inhibitor like marimastat or an inhibitor of urokinase plasminogen
activator receptor function); (iv) an inhibitor of growth factor
function, for example: a growth factor antibody (for example the
anti-erbb2 antibody trastuzumab, or the anti-erbb1 antibody cetuximab
[C225]), a farnesyl transferase inhibitor, a tyrosine kinase inhibitor or
a serine/threonine kinase inhibitor, an inhibitor of the epidermal growth
factor family (for example an EGFR family tyrosine kinase inhibitor such
as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoli-
n-4-amine (gefitinib, AZD1839),
N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine
(erlotinib, OSI-774) or
6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazoli-
n-4-amine (CI 1033)), an inhibitor of the platelet-derived growth factor
family, or an inhibitor of the hepatocyte growth factor family; (v) an
antiangiogenic agent such as one which inhibits the effects of vascular
endothelial growth factor (for example the anti-vascular endothelial cell
growth factor antibody bevacizumab, a compound disclosed in WO 97/22596,
WO 97/30035, WO 97/32856 or WO 98/13354), or a compound that works by
another mechanism (for example linomide, an inhibitor of integrin
αvβ3 function or an angiostatin); (vi) a vascular damaging
agent such as combretastatin A4, or a compound disclosed in WO 99/02166,
WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 or WO 02/08213; (vii)
an agent used in antisense therapy, for example one directed to one of
the targets listed above, such as ISIS 2503, an anti-ras antisense;
(viii) an agent used in a gene therapy approach, for example approaches
to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or
BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as
those using cytosine deaminase, thymidine kinase or a bacterial
nitroreductase enzyme and approaches to increase patient tolerance to
chemotherapy or radiotherapy such as multi-drug resistance gene therapy;
or (ix) an agent used in an immunotherapeutic approach, for example
ex-vivo and in-vivo approaches to increase the immunogenicity of patient
tumour cells, such as transfection with cytokines such as interleukin 2,
interleukin 4 or granulocyte-macrophage colony stimulating factor,
approaches to decrease T-cell anergy, approaches using transfected immune
cells such as cytokine-transfected dendritic cells, approaches using
cytokine-transfected tumour cell lines and approaches using
anti-idiotypic antibodies.

[0079] Some compounds of formula (I) may possess chiral centres. It is to
be understood that the invention encompasses the use of all such optical
isomers and diastereoisomers as well as compounds of formula (I) in any
of these forms, and pharmaceutical compositions containing compounds of
formula (I).

The invention further relates to all tautomeric forms of the compounds of
formula (IA) and pharmaceutical compositions containing these.

[0080] It is also to be understood that certain compounds of the formula I
can exist in solvated as well as unsolvated forms such as, for example,
hydrated forms. It is to be understood that the invention encompasses all
such solvated forms and pharmaceutical compositions containing these.

[0081] The compositions of the invention may be in a form suitable for
oral use (for example as tablets, lozenges, hard or soft capsules,
aqueous or oily suspensions, emulsions, dispersible powders or granules,
syrups or elixirs), for topical use (for example as creams, ointments,
gels, or aqueous or oily solutions or suspensions), for administration by
inhalation (for example as a finely divided powder or a liquid aerosol),
for administration by insufflation (for example as a finely divided
powder) or for parenteral administration (for example as a sterile
aqueous or oily solution for intravenous, subcutaneous, intermuscular or
intramuscular dosing or as a suppository for rectal dosing).

[0082] The compositions of the invention may be obtained by conventional
procedures using conventional pharmaceutical excipients, well known in
the art. Thus, compositions intended for oral use may contain, for
example, one or more colouring, sweetening, flavouring and/or
preservative agents.

[0083] Suitable pharmaceutically acceptable excipients for a tablet
formulation include, for example, inert diluents such as lactose, sodium
carbonate, calcium phosphate or calcium carbonate, granulating and
disintegrating agents such as corn starch or algenic acid; binding agents
such as starch; lubricating agents such as magnesium stearate, stearic
acid or talc; preservative agents such as ethyl or propyl
p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid. Tablet
formulations may be uncoated or coated either to modify their
disintegration and the subsequent absorption of the active ingredient
within the gastrointestinal tract, or to improve their stability and/or
appearance, in either case, using conventional coating agents and
procedures well known in the art.

[0084] Compositions for oral use may be in the form of hard gelatin
capsules in which the active ingredient is mixed with an inert solid
diluent, for example, calcium carbonate, calcium phosphate or kaolin, or
as soft gelatin capsules in which the active ingredient is mixed with
water or oil such as peanut oil, liquid paraffin, or olive oil.

[0085] Aqueous suspensions generally contain the active ingredient in
finely powdered form together with one or more suspending agents, such as
sodium carboxymethylcellulose, methylcellulose,
hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum
tragacanth and gum acacia; dispersing or wetting agents such as lecithin
or condensation products of an alkylene oxide with fatty acids (for
example polyoxyethylene stearate), or condensation products of ethylene
oxide with long chain aliphatic alcohols, for example
heptadecaethyleneoxycetanol, or condensation products of ethylene oxide
with partial esters derived from fatty acids and a hexitol such as
polyoxyethylene sorbitol monooleate, or condensation products of ethylene
oxide with partial esters derived from fatty acids and hexitol
anhydrides, for example polyethylene sorbitan monooleate. The aqueous
suspensions may also contain one or more preservatives (such as ethyl or
propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid),
colouring agents, flavouring agents, and/or sweetening agents (such as
sucrose, saccharine or aspartame).

[0086] Oily suspensions may be formulated by suspending the active
ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil
or coconut oil) or in a mineral oil (such as liquid paraffin). The oily
suspensions may also contain a thickening agent such as beeswax, hard
paraffin or cetyl alcohol. Sweetening agents such as those set out above,
and flavouring agents may be added to provide a palatable oral
preparation. These compositions may be preserved by the addition of an
anti-oxidant such as ascorbic acid.

[0087] Dispersible powders and granules suitable for preparation of an
aqueous suspension by the addition of water generally contain the active
ingredient together with a dispersing or wetting agent, suspending agent
and one or more preservatives. Suitable dispersing or wetting agents and
suspending agents are exemplified by those already mentioned above.
Additional excipients such as sweetening, flavouring and colouring
agents, may also be present.

[0088] The pharmaceutical compositions of the invention may also be in the
form of oil-in-water emulsions. The oily phase may be a vegetable oil,
such as olive oil or arachis oil, or a mineral oil, such as for example
liquid paraffin or a mixture of any of these. Suitable emulsifying agents
may be, for example, naturally-occurring gums such as gum acacia or gum
tragacanth, naturally-occurring phosphatides such as soya bean, lecithin,
and esters or partial esters derived from fatty acids and hexitol
anhydrides (for example sorbitan monooleate) and condensation products of
the said partial esters with ethylene oxide such as polyoxyethylene
sorbitan monooleate. The emulsions may also contain sweetening,
flavouring and preservative agents.

[0089] Syrups and elixirs may be formulated with sweetening agents such as
glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also
contain a demulcent, preservative, flavouring and/or colouring agent.

[0090] The pharmaceutical compositions may also be in the form of a
sterile injectable aqueous or oily suspension, which may be formulated
according to known procedures using one or more of the appropriate
dispersing or wetting agents and suspending agents, which have been
mentioned above. A sterile injectable preparation may also be a sterile
injectable solution or suspension in a non-toxic parenterally-acceptable
diluent or solvent, for example a solution in 1,3-butanediol.

[0091] Suppository formulations may be prepared by mixing the active
ingredient with a suitable non-irritating excipient, which is solid at
ordinary temperatures but liquid at the rectal temperature and will
therefore melt in the rectum to release the drug. Suitable excipients
include, for example, cocoa butter and polyethylene glycols.

[0092] Topical formulations, such as creams, ointments, gels and aqueous
or oily solutions or suspensions, may generally be obtained by
formulating an active ingredient with a conventional, topically
acceptable, vehicle or diluent using conventional procedure well known in
the art.

[0093] Compositions for administration by insufflation may be in the form
of a finely divided powder containing particles of average diameter of,
for example, 30μ or much less, the powder itself comprising either
active ingredient alone or diluted with one or more physiologically
acceptable carriers such as lactose. The powder for insufflation is then
conveniently retained in a capsule containing, for example, 1 to 50 mg of
active ingredient for use with a turbo-inhaler device, such as is used
for insufflation of the known agent sodium cromoglycate.

[0094] Compositions for administration by inhalation may be in the form of
a conventional pressurized aerosol arranged to dispense the active
ingredient either as an aerosol containing finely divided solid or liquid
droplets. Conventional aerosol propellants such as volatile fluorinated
hydrocarbons or hydrocarbons may be used and the aerosol device is
conveniently arranged to dispense a metered quantity of active
ingredient.

[0095] For further information on formulation the reader is referred to
Chapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin
Hansch; Chairman of Editorial Board), Pergamon Press 1990.

[0096] The amount of active ingredient that is combined with one or more
excipients to produce a single dosage form will necessarily vary
depending upon the host treated and the particular route of
administration. For example, a formulation intended for oral
administration to humans will generally contain, for example, from 0.5 mg
to 2 g of active agent compounded with an appropriate and convenient
amount of excipients, which may vary from about 5 to about 98 percent by
weight of the total composition. Dosage unit forms will generally contain
about 1 mg to about 500 mg of an active ingredient. For further
information on Routes of Administration and Dosage Regimes the reader is
referred to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry
(Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.

[0097] The size of the dose for therapeutic or prophylactic purposes of a
compound of the Formula (I) will naturally vary according to the nature
and severity of the conditions, the age and sex of the animal or patient
and the route of administration, according to well known principles of
medicine.

[0098] In using a compound of the Formula (I) for therapeutic or
prophylactic purposes it will generally be administered so that a daily
dose in the range, for example, 0.5 mg to 75 mg per kg body weight is
received, given if required in divided doses. In general lower doses will
be administered when a parenteral route is employed. Thus, for example,
for intravenous administration, a dose in the range, for example, 0.5 mg
to 30 mg per kg body weight will generally be used. Similarly, for
administration by inhalation, a dose in the range, for example, 0.5 mg to
25 mg per kg body weight will be used. Oral administration is however
preferred.

[0099] The compounds of the present invention are useful in therapy,
especially for the therapy of various pain conditions including, but not
limited to: acute pain, chronic pain, neuropathic pain, back pain, cancer
pain, and visceral pain. In a particular embodiment, the compounds are
useful in therapy for neuropathic pain. In an even more particular
embodiment, the compounds are useful in therapy for chronic neuropathic
pain.

[0100] In another embodiment, the compounds of the present invention may
be used to treat pain.

[0101] In another particular embodiment, the compounds of the present
invention may be used to treat neuropathic pain.

[0102] Particularly, there is provided a pharmaceutical composition
comprising a compound of Formula (I) or a pharmaceutically acceptable
salt thereof, in association with a pharmaceutically acceptable carrier
for therapy, more particularly for therapy of pain.

[0103] In use for therapy in a warm-blooded animal such as, for example, a
human, the compound of the present invention may be administered in the
form of a conventional pharmaceutical composition by any route including
orally, intramuscularly, subcutaneously, topically, intranasally,
intraperitoneally, intrathoracially, intravenously, epidurally,
intrathecally, transdermally, intracerebroventricularly and by injection
into the joints.

[0104] Within the scope of the invention is the use of any compound of
Formula (I) as defined above for the manufacture of a medicament.

[0105] Also within the scope of the invention is the use of any compound
of Formula (I) for the manufacture of a medicament for the therapy of
pain.

[0106] Additionally provided is the use of any compound according to
Formula (I) for the manufacture of a medicament for the therapy of
various pain conditions including, but not limited to: acute pain,
chronic pain, neuropathic pain, back pain, cancer pain, and visceral
pain.

[0107] A further aspect of the invention is a method for therapy of a
subject suffering from any of the conditions discussed above, whereby an
effective amount of a compound according to the Formula (I) above, is
administered to a patient in need of such therapy.

[0108] In a further aspect, the invention provides a method of treating
inflammatory disease by administering a compound of Formula (I) as
described above, or a pharmaceutical composition as described above.

[0109] Compounds of the invention having 2R stereochemistry (on the
piperazine ring) are a particular aspect of this invention.

[0110] The invention will now be illustrated by the following non-limiting
Examples in which, unless stated otherwise:

(i) temperatures are given in degrees Celsius (° C.); operations
were carried out at room or ambient temperature, that is, at a
temperature in the range of 18-25° C.; (ii) organic solutions were
dried over anhydrous magnesium sulfate; evaporation of solvent was
carried out using a rotary evaporator under reduced pressure (600-4000
Pascals; 4.5-30 mm Hg) with a bath temperature of up to 60° C.;
(iii) chromatography unless otherwise stated means flash chromatography
on silica gel; thin layer chromatography (TLC) was carried out on silica
gel plates (iv) in general, the course of reactions was followed by TLC
and reaction times are given for illustration only; (v) yields, when
given, are for illustration only and are not necessarily those which can
be obtained by diligent process development; preparations were repeated
if more material was required; (vi) when given, 1H NMR data is
quoted and is in the form of delta values for major diagnostic protons,
given in parts per million (ppm) relative to tetramethylsilane (TMS) as
an internal standard, determined at 400 MHz using perdeuterio DMSO
(CD3SOCD3) as the solvent unless otherwise stated; coupling
constants (J) are given in Hz; (vii) chemical symbols have their usual
meanings; SI units and symbols are used; (viii) solvent ratios are given
in percentage by volume; (ix) mass spectra (MS) were run with an electron
energy of 70 electron volts in the chemical ionisation (APCI) mode using
a direct exposure probe; where indicated ionisation was effected by
electrospray (ES); where values for m/z are given, generally only ions
which indicate the parent mass are reported, and unless otherwise stated
the mass ion quoted is the positive mass ion--(M+H).sup.+; (x) LCMS
characterisation was performed using a pair of Gilson 306 pumps with
Gilson 233 XL sampler and Waters Micromass ZQ mass spectrometer. The LC
comprised water symmetry 2×50 column C18 with 5 micron particle
size. The eluents were: A, water with 0.1% formic acid and B,
acetonitrile with 0.1% formic acid. The eluent gradient went from 95% A
to 95% B in 5 minutes. Where indicated ionisation was effected by
electrospray (ES); where values for m/z are given, generally only ions
which indicate the parent mass are reported, and unless otherwise stated
the mass ion quoted is the positive mass ion--(M+H).sup.+ and (xi) the
following abbreviations are used: DIPEA: diisopropylethylamine; DMSO:
dimethyl sulfoxide; DMF: N,N-dimethylformamide; DCM: dichloromethane;
EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; EtOAc:
ethyl acetate; eq: equivalent; g: gram; 1H NMR: proton nuclear
magnetic resonance; HATU:
O-(7-azabenzotriazol-lyl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate; HOBt: 1-hydroxybenzotriazole; m: multiplet; M:
molar; mL: milliliter; mg: milligram; MHz: megahertz; MeOH: methanol; RT:
retention time (HPLC); s: singlet; SCX: Strong Cation Exchange; t:
triplet; THF: tetrahydrofuran; TFA: trifluoroacetic acid; and TEA:
triethylamine

[0144] To a solution of tert-butyl
(2R)-4-tert-butyl-2-(piperazine-1-carbonyl)piperazine-1-carboxylate (340
mg) in THF (10 ml) was added TEA (201 μl) followed by phenyl
N-[5-chloro-4-(trifluoromethyl)-1,3-thiazol-2-yl]carbamate (310 mg) and
the resulting mixture was heated in a microwave oven (Biotage initiator)
at 60° C. for 1.5 hours. The reaction mixture was cooled and
concentrated. The residue was dissolved in DCM (10 ml), TFA (5 ml) was
added and the resulting mixture was stirred at room temperature for 1
hour. The reaction mixture was concentrated, dissolved in MeOH and poured
onto an SCX column. Elution with MeOH followed by 10% 7M NH3/MeOH in
MeOH gave crude product which is was further purified using silica
chromatography eluting with a gradient of MeOH/DCM (0-25%) to afford
title compound (415 mg). 1H NMR (400 MHz, CDCl3) δ ppm
1.06 (9H, s), 2.02-2.15 (2H, m), 2.82-2.94 (2H, m), 3.00 (1H, d),
3.06-3.13 (1H, m), 3.37-3.95 (10H, m). LCMS M/z(+) 483 (M+H.sup.+).

Intermediates

1: Preparation of Phenyl Carbamates

Phenyl N-(4-chloro-3-methylphenyl)carbamate

##STR00025##

[0146] To a solution of 4-chloro-3-methylaniline (2 g) in DCM (30 ml),
cooled to 0° C., was added pyridine (2.285 ml) followed by phenyl
chloroformate (1.85 ml) and the resulting mixture was stirred at room
temperature for 18 hours. 1M HCl (20 ml) was added and stirred for 10
minutes. The organic layer was washed with water and then brine. The
organic extracts were dried (MgSO4), and evaporated to give a gum.
The solid was slurried in hexane and filtered to give the titled compound
as a pale brown solid. 1H NMR (400 MHz, CDCl3) δ ppm 2.35
(3H, s), 7.15-7.40 (8H, m). LCMS M/z(+) 260 (M-H.sup.+).

[0147] In a similar manner, but using the appropriate aniline the
following carbamates were prepared:

[0158] A solution of 1-benzylpiperazine (1 g) and triethylamine (1.19 mL)
in THF (20 mL) was stirred at room temperature under argon. Acetyl
chloride (0.424 mL) was added and the reaction mixture was stirred for 10
minutes. The reaction was filtered and the white solid washed with ether.
The filtrate was concentrated at reduced pressure to give the title
compound (1.2 g). LCMS M/z(+) 219.07 (M+H.sup.+).

Step 2: Preparation of 1-Benzyl-4-tert-butylpiperazine

##STR00028##

[0160] A solution of 1-acetyl-4-benzylpiperazine (1.2 g) in THF was
stirred at -10° C. under argon. A 1M solution of titanium (V)
chloride (1.2 mL) was then added and the mixture was stirred for 30
minutes. A 3M solution of methylmagnesium bromide in ether (11.3 mL) was
then added dropwise and the black reaction mixture was warmed to ambient
temperature and stirred overnight. The reaction mixture was quenched with
30% aqueous sodium hydroxide solution and then partitioned between water
and dichloromethane. The layers were separated and the organic layer
washed with brine, dried (Na2SO4), filtered and concentrated.
The residue was purified on the Isco® Companion (40 g column: 0-10%
MeOH in DCM) to give the title compound (770 mg). LCMS M/z(+) 233.09
(M+H.sup.+).

[0162] A mixture of 1-benzyl-4-tert-butylpiperazine (740 mg),
di-tert-butyl dicarbonate (1.48 g) and 10% palladium on carbon (200 mg)
in ethanol (10 mL) was evacuated and purged with hydrogen three times and
then left under an atmosphere of hydrogen overnight at room temperature.
The mixture was filtered through a short pad of celite and concentrated
at reduced pressure. The residue was purified on the Isco® Companion
(40 g column 0-10% MeOH in DCM) to give the title compound (667 mg). LCMS
M/z(+) 243.09 (M+H.sup.+).

[0164] A solution of tert-butyl 4-tert-butylpiperazine-1-carboxylate (500
mg) and N,N,N',N'-tetramethylethylenediamine (0.467 mL) in ether (4 mL)
was stirred at -78° C. under argon. A 1.4 M solution of sec-butyl
lithium in cyclohexane (2.2 mL) was added dropwise and the mixture was
stirred at -78° C. for 3.5 hours. Carbon dioxide was then bubbled
through the reaction mixture via an argon purged syringe for 15 minutes
at -78° C. and then whilst warming to 0° C. The reaction
was quenched by the addition of water and then diluted with
dichloromethane, dried (Na2SO4), filtered and concentrated at
reduced pressure. The residue was purified on the Isco® Companion (40
g column: 0-20% MeOH in DCM) to give the title compound (370 mg).

[0167] To a solution of
1-(tert-Butoxycarbonyl)-4-tert-butylpiperazine-2-carboxylic acid (4.6 g),
1-benzylpiperazine (3.5 ml) and DIPEA (5.6 ml) in DMF (15 ml) at room
temperature was added HATU (6.1 g). After 2 hours water was added and the
mixture was stirred for 2 hours. The mixture was then partitioned between
ethyl acetate and water and the organic layer washed with brine
(×2), dried (Na2SO4) and concentrated at reduced
pressure. The residue was purified via silica column chromatography (120
g column) on the Isco companion eluting with a gradient methanol in ethyl
acetate (0 to 5%) to give title compound (4.5 g). LCMS M/z(+) 445
(M+H.sup.+).

[0171] Potassium cyanide (25.0 g, 1.0 eq) was added in one go to a
solution of N-Boc-piperazine (71.5 g, 1.0 eq) and para-toluenesulphonic
acid monohydrate (24.7 g, 1.0 eq) in water (715 ml) at 25° C.
Acetone (282 ml, 10 eq) was then added and the reaction mixture was
stirred at room temperature for 18 hours. The reaction mixture was
partitioned between saturated aqueous sodium hydrogen carbonate solution
(1000 ml) and ethylacetate (700 ml). The aqueous layer was separated and
extracted with ethylacetate (2×700 ml), the organics were combined,
dried (MgSO4), filtered and the solvent removed in vacuo. The
residue was purified by silica chromatography eluting with a gradient of
methanol in DCM (0 to 10%) to afford the title compound (52 g) as a white
solid.

[0174] Methylmagnesiumbromide (3M in diethylether) (317 ml, 3.0 eq) was
added dropwise over 30 minutes to a solution of tert-butyl
4-(2-cyanopropan-2-yl)piperazine-1-carboxylate (80 g, 1.0 eq) in THF (800
ml) at 15° C., exotherm seen 15° C.-28° C. The
reaction mixture was left stirred at room temperature for 18 hours. The
reaction was cooled to -10° C. and water (800 ml) was added
dropwise over 60 minutes (very exothermic -10° C.-25° C.).
Dichloromethane (1600 ml) was added and the organic layer was separated
and the aqueous layer extracted with dichloromethane (1600 ml). The
organics were combined and washed with 50% brine/water (1600 ml), dried
(MgSO4), filtered and the solvent removed in vacuo. The residue was
purified by silica chromatography eluting with ethyl acetate to afford
the title compound (48 g) as yellow solid.

[0177] sec-Butyllithium (1.4 M in cyclohexane) (38.3 ml, 1.3 eq) was added
dropwise over 20 minutes to a stirred solution of tert-butyl
4-tert-butylpiperazine-1-carboxylate (10 g, 1.0 eq) and (-)-sparteine
(12.3 ml, 1.3 eq) in diethylether (300 ml) at -78° C.
(acetone/solid carbon dioxide bath) under an atmosphere of nitrogen,
keeping the internal temperature below -70° C., the reaction was
left stirring for 4 hours at -78° C. before carbon dioxide gas was
bubbled through the reaction (exothermic -78° C.--66° C.)
for 1 hour (using dry ice). The reaction was allowed to warm to room
temperature and stirred for 18 hours. Water (10 ml) was then added
dropwise to quench the reaction (no exotherm seen). Dichloromethane (200
ml) was added to dilute followed by sodium sulphate. The reaction was
stirred for 10 minutes then filtered washing through with dichloromethane
(200 ml) (slow filtration). The solvent was then removed in vacuo to give
the crude carboxylic acid (24.5 g), which used in the next step without
further purification. (Chiral analysis of crude material showed compound
to have ˜65% ee).

[0182] To a solution of tert-butyl
(2R)-2-(4-benzylpiperazine-1-carbonyl)-4-tert-butylpiperazine-1-carboxyla-
te (10 g) in ethanol (100 ml) was added 10% Palladium on carbon (50% wet,
2 ml), and the resulting mixture was hydrogenated at 5 barr at 35°
C. for 18 hours. The reaction mixture was filtered and concentrated. The
resulting gum was titrated with isohexane and filtered to give the titled
compound (7.9 g) as a white solid.

[0184] To a solution of tert-butyl piperazine-1-carboxylate (198 mg) in
DCM (10 ml) was added TEA (444 μl) followed by phenyl
N-(5-chloro-4-ethyl-1,3-thiazol-2-yl)carbamate (299 mg) and the resulting
mixture was heated at 60° C. for 1 hour. The mixture was washed
with water and the organics were dried (MgSO4), filtered and
concentrated under reduced pressure. The residue was purified by silica
chromatography eluting with a gradient of EtOAc/isohexane (0 to 50%). The
resulting product was dissolved in DCM (5 ml), TFA (2 ml) was added and
the resulting mixture was stirred at room temperature for 2 hours. The
reaction mixture was transferred to a SCX column and eluted with
methanol, followed by 10% 7N NH3 in methanol to afford the titled
compound (90 mg).

[0186] In a similar manner, but using the appropriate carbamates the
desired piperazine ureas were prepared.

Pain Models

CCR2b Antagonist Behavioural Experimental Procedures

Induction of Rat Spinal Nerve Ligated (SNL) Model of Neuropathic Pain

[0187] Under isoflurane anesthesia, an incision is made dorsal to the
lumbosacral plexus. The paraspinal muscles (left side) are separated from
the spinous processes, the L5 and L6 spinal nerves are isolated and
tightly ligated with (4-0 silk suture) distal to the dorsal root ganglion
and prior to entrance into the sciatic nerve. The incision is closed and
the skin is sealed with tissue adhesive. Rats are allowed to recover and
then placed in cages with soft bedding. All experiments are conducted
between postoperative day 7 to day 44.

[0188] Under isoflurane anesthesia, a small incision is made 0.5 cm below
the pelvis. The biceps femoris and the gluteus superficialis (left side)
are separated. The sciatic nerve is exposed, isolated and four loose
ligatures (4-0 chromic gut) with 1 mm spacing are placed around it. The
nerve is then placed back in its natural position, and the incision is
sealed. Rats are allowed to recover and then placed in a cage with soft
bedding. All experiments are conducted between postoperative day 7 to day
44.

Assessment of Neuropathic-Induced (SNL or CCI) Heat Hyperalgesia

[0189] In order to assess the degree of heat hyperalgesia, rats are
individually placed in Plexiglas boxes on a glass surface (maintained at
30° C.) of the paw thermal stimulator system (IITC Life Science,
Woodland Hills, USA, Model 390, Series 8), and allowed to acclimatize for
30 minutes. A thermal stimulus, in the form of a radiant heat beam, is
focused onto the plantar surface of the affected paw. In each test
session, rats are tested twice approximately 5 minutes apart. Paw
withdrawal latencies (PWLs) are calculated as the mean of the 2 values.
An assay cut off is set at 20 seconds. In all experiments, animals are
tested before drug administration to ensure stable heat-hyperalgesia
baseline.

[0190] Mechanical hyperalgesia is assessed using the Ugo Basile
analgesy-meter (Ugo Basile, Comerio, Italy). Animals are gently
restrained, and a steadily increasing pressure is applied to the dorsal
surface of a hind paw via a dome-shaped tip (diameter of 1 mm) The
pressure requires to elicit paw withdrawal (PWT: paw withdrawal
threshold) is determined. An assay cutoff is set at 295 g. In all
experiments, animals are tested before drug administration to ensure
stable mechanical hyperalgesia baseline.

Drug Treatment:

[0191] A study typically consists of 5 groups. One group is naive and
serves as a baseline control. The other 4 groups undergo surgery to
induce nerve injury. One of the groups serves as a vehicle control while
the remaining 3 groups are treated with drug of increasing dose
concentration. Test compound is administered orally and is tested for
heat and/or mechanical hyperalgesia 240 minutes later. In all cases, the
experimenter is blind to the treatment.

Bioanalysis:

[0192] Satellite animals are used for plasma and brain tissue collection.
Animals are injected with drug but were not subjected to any testing.
Blood and brain are collected by decapitation without anesthesia at the
appropriate time point.

Data Analysis

[0193] Statistical significance is determined using two-way RM ANOVA using
raw data followed by a post-hoc Holm-Sidak t-test. The level of
statistical significance is set at p<0.05. GraphPad Prism® Version
4 is used for non-linear regression analysis. Raw data is converted using
the following formula:

% anti-hyperalgesia=(PWL or PWT(dosed)-PWL or PWT(vehicle))/(PWL or
PWT(naive)-PWL or PWT(vehicle))×100.

[0194] Data is expressed as mean±SEM. The 50% effective dose and blood
plasma concentration are calculated from the best-fit curve using the
variable slope sigmoidal equation model.

[0197] Test compounds were dissolved in DMSO and further diluted in assay
buffer (50 mM HEPES, 1 mM CaCl2, 5 mM MgCl2, 1 mM EDTA, 0.03%
BSA, pH 7.2) to give a range of concentrations starting with a top final
concentration of up to 10 μM. All incubations had a 100 μl final
volume and a DMSO concentration of 1%. Incubations contained 250 μM
125I-labeled MCP-1 (GE Healthcare), 0.5 mg Scintillation proximity
assay beads (GE Healthcare RPNQ001) and cell membranes containing
6×106 cells/ml equivalent. Non-specific binding was determined
by the inclusion of 10 μM of a known CCR2b antagonist in the place of
test compound. Total binding was determined in the presence of 1% DMSO
without compound. Incubations were performed in sealed optiplates and
kept at room temperature for 16 hours after which the plates were counted
on a Packard TopCount (Packard TopCount®). Dose-response curves were
generated using "in-house" data analysis package incorporating Origin
software to determine IC50 values. Percent inhibitions were
calculated for single concentrations of compound by using the following
formula 100-((compound binding minus non-specific binding)/(total binding
minus non-specific binding)×100).

[0198] Each compound set out in the Examples below was tested as above and
shown to have an IC50 value of better than 20 μM